HK1079511B - Diphenyl azetidinones substituted by acidic groups, method for their production, medicaments containing said compounds and use thereof - Google Patents

Description

diphenylazetidinones substituted by acidic groups, method for the production thereof, medicaments containing them and the use thereof

The invention relates to acid group substituted diphenyl azetidinones, their physiologically acceptable salts and physiologically functional derivatives.

Diphenylazetidinones (e.g., ezetimibe) and their use in the treatment of hyperlipidemia and atherosclerosis and hypercholesterolemia have been described [ see Drugs of the Future 2000, 25 (7): 679 685 and US 5,756,470 ].

It is an object of the present invention to provide other compounds having therapeutically useful hypolipidemic effects. In particular, it is an object of the present invention to find new compounds which absorb to a very low degree compared to the compounds described in the prior art. Very low absorption is understood to mean an intestinal absorption of less than 10%, preferably less than or equal to 5%.

In particular, the absorption of the new compounds must be less than ezetimibe. Pharmaceutically active compounds that are absorbed to a lesser extent generally have much fewer side effects.

Accordingly, the present invention relates to compounds of the formula I

Wherein

R1, R2, R3, R4, R5 and R6 are independently (C)₀-C₃₀) Alkylene radicals (LAG)_nWherein n may be 1-5 and wherein one or more carbon atoms of the alkylene group may be replaced by-S (O)_n-, where N ═ 0-2, -O-, - (C ═ O) -, - (C ═ S) -, - (CH ═ CH-, -C ≡ C-, -N ((C ≡ C) -, in which the radicals are substituted with one or more carbon atoms₁-C₆) -alkyl) -, -N (phenyl), -N ((C)₁-C₆) -alkyl-phenyl) -, -N (CO- (CH)₂)_1-10-COOH) -or-NH-substitution;

H、F、Cl、Br、I、CF₃、NO₂、N₃、CN、COOH、COO(C₁-C₆) Alkyl, CONH₂、CONH(C₁-C₆) Alkyl, CON [ (C)₁-C₆) -alkyl radical]₂、(C₁-C₆) Alkyl radicals, (C)₂-C₆) -alkenyl, (C)₂-C₆) Alkynyl, O- (C)₁-C₆) -alkyl, wherein one, more or all of the hydrogens of the alkyl group may be replaced by fluorine;

C(＝NH)(NH₂)、PO₃H₂、SO₃H、SO₂-NH₂、SO₂NH(C₁-C₆) Alkyl, SO₂N[(C₁-C₆) -alkyl radical]₂、S-(C₁-C₆) Alkyl, S- (CH)₂)_n-phenyl, SO- (C)₁-C₆) Alkyl, SO- (CH)₂)_n-phenyl, SO₂-(C₁-C₆) -an alkyl group,SO₂-(CH₂)_nPhenyl, where n is 0-6 and the phenyl group may be substituted by F, Cl, Br, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂Substitution is at most two times;

NH₂、NH-(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、NH(C₁-C₇) -acyl, phenyl, O- (CH)₂)_nPhenyl, where n may be 0 to 6, in which the phenyl ring may be substituted by F, Cl, Br, I, OH, CF₃、NO₂、CN、OCF₃、O-(C₁-C₆) Alkyl radicals, (C)₁-C₆) -alkyl, NH₂、NH-(C₁-C₆) Alkyl, N ((C)₁-C₆) -alkyl groups)₂、SO₂-CH₃、COOH、COO-(C₁-C₆) Alkyl, CONH₂Mono-to tri-substituted;

(LAG)_nis- (CH)₂)_1-10-SO₃H、-(CH₂)_0-10-P(O)(OH)₂、(CH₂)_0-10-O-P(O)(OH)₂、-(CH₂)_0-10-COOH and n may be 1-5;

wherein at least one of the radicals R1-R6 must in each case have a (C)₀-C₃₀) Alkylene- (LAG)_nWherein n is 1-5 and wherein one or more carbon atoms of the alkylene group is replaced by-S (O)_n-, where N ═ 0-2, -O-, - (C ═ O) -, - (C ═ S) -, - (CH ═ CH-, -C ≡ C-, -N ((C ≡ C) -, in which the radicals are substituted with one or more carbon atoms₁-C₆) -alkyl) -, -N (phenyl), -N ((C)₁-C₆) -alkyl-phenyl) -, -N (CO- (CH)₂)_1-10-COOH) -or-NH-substitution; but excluding the compound 2- { [4- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]-4-oxoazetidin-2-yl } phenoxy) butyl]Methylamino } ethanesulfonic acid and where the radicals R1-R6 have the meaning-O- (CH)₂)_1-10-COOH、(C₁-C₆) alkylene-COOH or-CCompound with the meaning of OOH.

Preferred are compounds of formula I: wherein at least one of the radicals R1-R6 has (C)₀-C₃₀) -alkylene- (LAG), wherein one or more carbon atoms of the alkylene group may be replaced by-O-, - (C ═ O) -, -N ((C ═ O) -)₁-C₆) -alkyl) -, -N (CO- (CH)₂)_1-10-COOH) -or-NH-substitution.

Particular preference is given to compounds of the formula I: wherein one of the radicals R1 or R3 has (C)₀-C₃₀) -alkylene- (LAG), wherein one or more carbon atoms of the alkylene group may be replaced by-O-, - (C ═ O) -, -N (CH)₃) -or-NH-substitution.

Very particular preference is given to compounds of the formula I: wherein one of the radicals R1 or R3 has- (CH)₂)_0-1-Y-W-(C₀-C₂₅) -alkylene-Y '-W' - (LAG) meaning; wherein one or more carbon atoms of the alkylene group may be replaced by oxygen atoms and wherein Y and W independently of each other may be NH, NCH₃O, O, one bond or S (O)_nWhere n ═ 0-2, Y 'and W' may, independently of one another, be NH, NCH₃O, O, one bond or S (O)_nWherein n-0-2, or Y-W or Y '-W', respectively, may be taken together as a bond.

Further preferred are compounds of formula I wherein the group LAG is a carboxylic acid group or a sulfonic acid group.

Pharmaceutically acceptable salts are particularly suitable for pharmaceutical use due to their increased solubility in water compared to the parent compound. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the invention are salts of inorganic acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and salts of organic acids, such as acetic, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic and tartaric acids. Suitable pharmaceutically acceptable base salts are ammonium salts, alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. magnesium and calcium salts), tromethamine (2-amino-2-hydroxymethyl-1, 3-propanediol), diethanolamine, lysine or ethylenediamine salts.

Salts with a non-pharmaceutically acceptable anion, such as trifluoroacetate, are also within the scope of the invention and are useful as intermediates for the preparation or purification of pharmaceutically acceptable salts and/or for non-therapeutic uses, such as in vitro applications.

The term "physiologically functional derivative" is intended to mean any physiologically acceptable derivative of a compound of the invention, for example an ester which, upon administration to a mammal such as a human, produces (directly or indirectly) said compound or an active metabolite thereof.

Another aspect of the present invention includes prodrugs of the compounds of the present invention. The prodrugs can be metabolized in vivo to compounds of the invention. These prodrugs may or may not be active themselves.

The compounds of the invention may also exist in different polymorphic forms, for example amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds of the present invention are within the scope of the present invention and are a further aspect of the invention.

Hereinafter, "compounds of formula (I)" each means a compound of the above formula (I) and salts, solvates and physiologically functional derivatives thereof.

The compounds of formula I and their pharmaceutically acceptable salts and physiologically functional derivatives are ideal drugs for the treatment of impaired lipid metabolism, in particular hyperlipidemia. The compounds of formula I are also suitable for modulating serum cholesterol concentrations and for preventing and treating the clinical manifestations of atherosclerosis.

The compounds of formula (I) may also be administered in combination with other active compounds.

The amount of a compound of formula I required to achieve the desired biological effect will depend on a variety of factors, such as the particular compound selected, the intended use, the mode of administration and the clinical condition of the patient. Generally, the daily dose will be in the range 0.1mg to 100mg (typically 0.1mg to 50mg) per day per kg of body weight, for example 0.1 to 10 mg/kg/day. Tablets and capsules may contain, for example, 0.01 to 100mg, typically 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the weight data set forth above is the weight of diphenylazetidinone ion derived from the salt. For the prevention or treatment of the above-mentioned conditions, the compounds of formula (I) may be used as such, but preferably they are present in the form of a pharmaceutical composition in association with an acceptable carrier. The carrier should obviously be acceptable, i.e. compatible with the other components of the composition and not harmful to the health of the patient. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example, as a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances, including other compounds of formula I, may also be present. The pharmaceutical compositions of the present invention may be prepared using known pharmaceutical methods, which essentially comprise mixing the components with pharmaceutically acceptable carriers and/or excipients.

The pharmaceutical compositions of the invention are those suitable for oral or peroral (sublingual) administration, although the most suitable mode of administration will depend in each particular case on the nature and severity of the condition being treated and on the type of compound of formula I used in each case. Coated formulations and coated delayed release formulations are also within the scope of the invention. Acid resistant and enteric formulations are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyethylene acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methacrylate esters.

Pharmaceutical compounds suitable for oral administration may be presented as discrete units such as capsules, cachets, lozenges, or tablets, each containing a defined amount of a compound of formula I; powder or granules; such as solutions or suspensions in aqueous or non-aqueous liquids; or for example an oil-in-water or water-in-oil emulsion. As noted above, these compositions may be prepared using any suitable pharmaceutical method including the step of bringing into contact the active compound and the carrier, which may consist of one or more additional ingredients. Generally, the compositions are prepared by homogeneously and homogeneously mixing the active compounds with liquid and/or finely divided solid carriers, after which, if desired, the product is shaped. Thus, for example, a tablet may be formed by compressing or molding a powder or granules of the compound with the appropriate additional ingredient or ingredients. Compressed tablets may be prepared by compressing in a suitable apparatus the compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or one or more surface active/dispersing agents. Molded tablets may be made by molding the powdered compound moistened with an inert liquid diluent in a suitable apparatus.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges comprising a compound of formula (I) and a flavouring agent, usually sucrose and acacia or tragacanth; and pastilles comprising the compound in an inert base such as gelatin and glycerin or sucrose and acacia.

Other active compounds suitable for use in the combined preparation are: all antidiabetic drugs mentioned in Roten list 2001, chapter 12. They can be combined with the compounds of the formula I according to the invention, in particular for a synergistic effect. The combination of active compounds can be administered to the patient by separate administration of the active compounds or in the form of a combined preparation containing several active compounds in a single pharmaceutical preparation.

Antidiabetic agents include insulin and insulin derivatives, e.g., LantusOr HMR1964, GLP-1 derivatives such as those disclosed in Novo Nordisk A/S in WO 98/08871, and orally hypoglycemic active compounds. The orally hypoglycemic active compounds preferably include sulfonylureas, biguanides, meglitinides, oxadiazolidinediones, thiazolidinediones, glycosidase inhibitors, glucagon antagonists, GLP-1 agonists, calcium channel openers,such as those disclosed by NovoNordisk a/S in WO 97/26265 and WO99/03861, insulin sensitizers, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which alter lipid metabolism, such as antihyperlipidemic and antilipidemic active compounds, compounds which reduce food intake, agonists of PPAR and PXR and active compounds which act on the ATP-dependent potassium channel of beta cells.

In one embodiment of the invention, the compound of formula I is administered in combination with an HMGCoA-reductase inhibitor, such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, Rosuvastatin (Rosuvastatin).

In one embodiment of the invention, the compounds of formula I are administered in combination with a cholesterol absorption inhibitor, e.g. ezetimibe, tiquinazine, pamabrin.

In one embodiment of the invention, the compound of formula I is administered in combination with a PPAR γ agonist, such as rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compounds of formula I are administered in combination with a PPAR α agonist, e.g., GW 9578, GW 7647.

In one embodiment of the invention, the compounds of formula I are administered in combination with a mixed PPAR α/γ agonist, for example GW 1536, AVE 8042, AVE 8134 or AVE 0847.

In one embodiment of the invention, the compound of formula I is administered in combination with a fibrate, e.g., fenofibrate, clofibrate, bezafibrate.

In one embodiment of the invention, the compound of formula I is administered in combination with an MTP inhibitor, such as Bay 13-9952, BMS-201038, or R-103757.

In one embodiment of the invention, the compound of formula I is administered in combination with a bile acid absorption inhibitor, such as HMR 1453.

In one embodiment of the invention, the compound of formula I is administered in combination with a CETP inhibitor, such as Bay 194789.

In one embodiment of the invention, the compound of formula I is administered in combination with a polymeric bile acid adsorbent, such as cholestyramine and Colesolvam.

In one embodiment of the invention, the compound of formula I is administered in combination with an LDL-receptor inducing agent, e.g. HMR1171, HMR 1586.

In one embodiment of the invention, the compounds of formula I are administered in combination with an ACAT inhibitor, such as avasimibe (avasimibe).

In one embodiment of the invention, the compound of formula I is administered in combination with an antioxidant, such as OPC-14117.

In one embodiment of the invention, the compounds of formula I are administered in combination with a lipoprotein lipase inhibitor, e.g., NO-1886.

In one embodiment of the invention, the compound of formula I is administered in combination with an ATP-citrate lyase inhibitor, such as SB-204990.

In one embodiment of the invention, the compound of formula I is administered in combination with a squalene synthetase inhibitor, e.g., BMS-188494.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein (a) antagonist, such as CI-1027 or niacin.

In one embodiment of the invention, the compound of formula I is administered in combination with a lipase inhibitor, e.g. orlistat.

In one embodiment of the invention, the compound of formula I is administered in combination with insulin

In one embodiment of the invention, the compounds of formula I are administered in combination with a sulfonylurea, for example tolbutamide, glibenclamide, glipizide or glimepiride.

In one embodiment of the invention, the compound of formula I is administered in combination with a biguanide, for example metformin.

In yet another embodiment, the compound of formula I is administered in combination with a meglitinide, such as repaglinide.

In one embodiment, the compound of formula I is administered in combination with a thiazolidinedione, such as troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097(dr. reddy's Research Foundation), in particular 5- [ [4- [ (3, 4-dihydro-3-methyl-4-oxo-2-quinazolinyl) methoxy ] -phenyl ] methyl ] -2, 4-thiazolidinedione.

In one embodiment, the compound of formula I is administered in combination with an α -glucosidase inhibitor, such as miglitol or acarbose.

In one embodiment, the compounds of formula I are administered in combination with an active compound that acts on the ATP-dependent potassium channel of beta cells, such as tolbutamide, glyburide, glipizide, glimepiride or repaglinide.

In one embodiment, the compound of formula I is administered in combination with more than one of the above compounds, for example in combination with sulfonylureas and metformin, with sulfonylureas and acarbose, with repaglinide and metformin, with insulin and sulfonylureas, with insulin and metformin, with insulin and troglitazone, with insulin and lovastatin, and the like.

In another embodiment, the compounds of formula I are administered with a CART agonist, NPY agonist, MC3 and MC4 agonist, orexin (orexin) agonist, H3 agonist, TNF agonist, CRF BP antagonist, urocortin agonist, β 3-agonist, MCH (melanin concentrating hormone) antagonist, CCK agonist, 5-hydroxytryptamine reuptake inhibitor, mixed 5-hydroxytryptamine and noradrenaline compounds, 5HT agonist, bombesin agonist, galanin (galanin) antagonist, growth hormone releasing compound, TRH agonist, uncoupling protein 2-or 3-modulator, leptin (leptin) agonist, DA agonist (bromocriptine, doprexin), lipase/amylase inhibitor, PPAR modulator, RXR modulator, or TR- β agonist.

In one embodiment of the invention, the additional active compound is leptin.

In one embodiment, the additional active compound is dextroamphetamine or amphetamine.

In one embodiment, the additional active compound is fenfluramine or dexfenfluramine

In another embodiment, the additional active compound is sibutramine.

In one embodiment, the additional active compound is orlistat

In one embodiment, the additional active compound is mazindol or phentermine.

In one embodiment, the compounds of formula I are administered in combination with fibers, especially insoluble fibers, for example. Andthe combination can be administered by either administering a single formulation or separately administering a compound of formula I andto be implemented.It may also be administered in the form of a food, for example, taken in a bread product or a milkbreakfast bar. The compounds of the formula I are compared with the individual active compoundsIn combination with features of improved tolerability, in addition to an enhancing effect, in particular in terms of lowering LDL cholesterol。

Needless to say, various suitable combinations of a compound of the invention with one or more of the above compounds and optionally one or more other pharmaceutically active substances are within the scope of the invention.

The invention also provides a mixture of stereoisomers of formula I and pure stereoisomers of formula I, as well as mixtures of diastereomers of formula I and pure diastereomers. The mixture can be separated by chromatography.

Preferred are racemic and enantiomerically pure compounds of formula I having the structure:

the amino-protecting group preferably used is a benzyloxycarbonyl (Z) group, which can be removed by catalytic hydrogenation; 2- (3, 5-dimethoxyphenyl) propyl (2) oxycarbonyl (Ddz) or trityl (Trt) groups, which can be removed with a weak acid; a tert-butyl carbamate (BOC) group which can be removed under the action of 3M hydrochloric acid; and a 9-fluorenylmethoxycarbonyl (Fmoc) group, which can be removed with a secondary amine.

The invention further relates to a process for preparing diphenylazetidinone derivatives of the formula I.

Y may be S, O, (C ═ O), (C ═ S), CH ═ CH, C ≡ C, N ((C ≡ C, N)₁-C₆) Alkyl, N (phenyl), N ((C)₁-C₆) Alkyl-phenyl), N (CO- (CH)₂)_1-10-COOH) or NH;

r11 may be H or OH when Y ═ O or (C ═ S);

w, Y 'and W' may be independent of each other and independently of Y-S(O)_n-, where N ═ 0-2, -O-, - (C ═ O) -, - (C ═ S) -, - (CH ═ CH-, -C ≡ C-, -N ((C ≡ C) -, in which the radicals are substituted with one or more carbon atoms₁-C₆) -alkyl) -, -N (phenyl) -, -N ((C)₁-C₆) -alkyl-phenyl) -, -N (CO- (CH)₂)_1-10-COOH) -or-NH-or a bond; x, y and z independently of one another may be 0 to 10.

In the compound II, - (CH)₂)_x-Y-R11 may also be attached to one of the other two phenyl rings.

The process for preparing the compounds of the formula I comprises, for example, reacting the amine or hydroxy compounds of the formula II with alkylating or acylating agents which preferably bear further functional groups in the ω -position, if appropriate in protected form. This functional group (after deprotection) is used for Ligation (LAG), e.g. to form ether, amine or amide bonds.

The following examples are intended to illustrate the invention in detail, but are not intended to limit the invention to the products and embodiments described in the examples.

Example I

4- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) 4-oxoazetidin-1-yl ] benzylamino } butane-1-sulfonic acid (6):

a)3- [5- (tert-butyldimethylsilyloxy) -5- (4-fluorophenyl) -pentanoyl ] 4-phenyl-oxazolidin-2-one (1):

27g of 3- [5- (4-fluorophenyl) -5-hydroxypentanoyl]4-Phenyloxazolidin-2-one, 13.6g of tert-butyldimethylchlorosilane and 10.2g of imidazole were dissolved in 36ml of dimethylformamide and stirred at 60 ℃Stirring for 90 minutes. After the reaction was completed, the mixture was dissolved in ethyl acetate and extracted 2 times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This gives 3- [5- (tert-butyldimethylsilyloxy) -5- (4-fluorophenyl) -pentanoyl]-4-phenyloxazolidin-2-one (1) with molecular weight 471.65 (C)₂₆H₃₄FNO₄Si)；MS(ESI)：340.28(MH⁺-HOSi(CH₃)₂C(CH₃)₃)。

b)4- [5- (tert-butyldimethylsilyloxy) -5- (4-fluorophenyl) -1- (4-methoxyphenyl) -2- (2-oxo-4-phenyloxazolidine-3-carbonyl) pentylamino ] benzonitrile (2):

16.2g of 3- [5- (tert-butyldimethylsilyloxy) -5- (4-fluorophenyl) -pentanoyl]4-Phenyloxazolidin-2-one was dissolved in 350ml dichloromethane. 19.8ml of Hunig's base and 10.14g of 4- [ (4-methoxyphenylimino) methyl group were added]Benzonitrile, and the solution was cooled to-10 ℃. To the cooled solution was added 8.52ml of trimethylsilyl triflate and the mixture was stirred at-10 ℃ for 30 minutes. The solution was then cooled to-30 ℃ and 44ml of titanium tetrachloride solution was added. The reaction mixture was stirred at-30 ℃ to-40 ℃ for 2 hours. Thereafter, the solution was allowed to warm to room temperature and the reaction solution was washed with 200ml of 2N sulfuric acid, 300ml of a 20% sodium bisulfite solution and a saturated sodium chloride solution in this order. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified on silica gel with n-heptane/ethyl acetate 3/1. To obtain 4- [5- (tert-butyl dimethyl silicon alkoxy) -5- (4-fluorophenyl) -1- (4-methoxyphenyl) -2- (2-oxo-4-phenyl oxazolidine-3-carbonyl) pentylamino]Benzonitrile having a molecular weight of 707.93 (C)₄₁H₄₆FN₃O₅Si)；MS(ESI)：590.51(MH⁺-C₇H₅N₂)。

c)4- [3- [3- (tert-butyldimethylsilyloxy) -3- (4-fluorophenyl) propyl ] -2- (4-methoxyphenyl) -4-oxoazetidin-1-yl ] benzonitrile (3):

13.2g of 4- [5- (tert-butyldimethylsilyloxy) -5- (4-fluorophenyl) -1- (4-methoxy)Phenyl) -2- (2-oxo-4-phenyloxazolidine-3-carbonyl) pentylamino]Benzonitrile is dissolved in 380ml of methyl tert-butyl ether, 18.6ml of N, O-bis (trimethylsilyl) acetamide and 1.86ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 hours. After the end of the reaction, 10ml of acetic acid were added, the reaction mixture was concentrated under reduced pressure and the residue was purified on silica gel with toluene/ethyl acetate 50/1. To obtain 4- [3- [3- (tert-butyldimethylsilyloxy) -3- (4-fluorophenyl) propyl group]-2- (4-methoxyphenyl) -4-oxoazetidin-1-yl]Benzonitrile (3), molecular weight 544.75 (C)₃₂H₃₇FN₂O₃Si)；MS(ESI)：545.56(M+H⁺)。

d)4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) 4-oxoazetidin-1-yl ] benzonitrile (4):

3.5g of 4- [3- [3- (tert-butyldimethylsilyloxy) -3- (4-fluorophenyl) propyl ] are reacted]-2- (4-methoxyphenyl) -4-oxoazetidin-1-yl]Benzonitrile is dissolved in 65ml of tetrahydrofuran, 0.74ml of acetic acid and 8.03ml of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at room temperature for 2 hours. 4.82ml of tetrabutylammonium fluoride solution were subsequently added and the mixture was stirred at reflux temperature for a further 3 hours. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography with n-heptane/ethyl acetate 2/1. To obtain 4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl]-2- (4-methoxyphenyl) -4-oxoazetidin-1-yl]Benzonitrile (4), molecular weight 430.48 (C)₂₆H₂₃FN₂O₃)；MS(ESI)：431.24(M+H⁺)。

e)1- (4-aminomethylphenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4- (4-methoxyphenyl) -azetidin-2-one (5):

1.22g of 4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl]-2- (4-methoxyphenyl) -4-oxoazetidin-1-yl]Benzonitrile is dissolved in 90ml of ethanol, 10ml of concentrated ammonia solution and an excess of Raney nickel are added and the mixture is stirred at 60 ℃ under a hydrogen pressure of 10 bar for 8 hours. Overnight, the reaction mixture was cooled to room temperature, the next day, the crystals were removed, the filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel with dichloromethane/methanol/ammonia solution 10/1/0.1. To obtain 1- (4-aminomethyl phenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]-4- (4-methoxyphenyl) -azetidin-2-one (5) with a molecular weight of 434.51 (C)₂₆H₂₇FN₂O₃)；MS(ESI)：418.2(MH⁺-NH₃)。

f)4- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) 4-oxo-azetidin-1-yl ] benzylamino } butane-1-sulfonic acid (6):

87mg of the above benzylamine are dissolved in 3ml of dry acetonitrile at room temperature, 40. mu.l of 1, 4-butane sultone are added and the mixture is heated at reflux for 12 hours. The cooled reaction solution was concentrated under reduced pressure and purified by chromatography (silica gel; dichloromethane/methanol 85/15+ 10% water). Obtaining 4- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl]-2- (4-methoxyphenyl) -4-oxo-azetidin-1-yl]Benzylamino } butane-1-sulfonic acid (6), molecular weight 570.69 (C)₃₀H₃₅FN₂O₆S)；MS(ESI)：553.28(MH⁺-H₂O)。

Example II

2- [ (4- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) 4-oxoazetidin-1-yl ] phenoxy } butyl) methylamino ] ethanesulfonic acid (8):

130mg of 3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -1- [4- (4-fluorobutoxy) phenyl ] -4- (4-methoxyphenyl) azetidin-2-one (7) are dissolved in 6ml of absolute methanol. After which 120mg of N-methyltaurine in 2ml of water and 60mg of potassium carbonate are added. The mixture was stirred at 50 ℃ for 24 hours. The reaction mixture was concentrated with a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying afforded the product as an oil (50 mg).

C₃₂H₃₉FN₂O₇S ESIMS m/z：614(M⁺)

Example 1II

[2- (4- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) -4-oxoazetidin-1-yl ] phenoxy } butylamino) ethyl ] phosphoric acid (9):

200mg of 3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -1- [4- (4-fluorobutoxy) phenyl ] -4- (4-methoxyphenyl) azetidin-2-one (7) are dissolved in 6ml of absolute methanol. 165mg of 1-aminoethyl phosphate and 247mg of potassium carbonate dissolved in 3ml of water are added. The mixture was stirred at 90 ℃ for 8 hours. The reaction mixture was concentrated with a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying afforded the product as an oil (47 mg).

C₃₁H₃₈FN₂O₇P ESIMS m/z：600(M⁺)

Example IV

Mono- {6- [4- (4- {1- (4-fluorophenyl) 3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxoazetidin-2-yl } phenoxy) butylamino ] hexyl } phosphate (10):

115mg of 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4- [4- (2-fluoromethoxyethoxy) phenyl ] azetidin-2-one (7) are dissolved in 6ml of absolute methanol. 130mg of 6-amino-1-hexyl phosphate and 107mg of potassium carbonate in 1.5ml of water are then added. The mixture was stirred at 70 ℃ overnight. The reaction mixture was concentrated with a rotary evaporator and the residue was purified by preparative chromatography. Freeze drying gave an oily product.

C₃₄H₄₃F₂N₂O₇P ESIMS m/z：660(M⁺)

Example V

4- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) -4-oxoazetidin-1-yl ] phenoxy } butane-1-sulfonic acid (12):

160mg of 3- [3- (4-fluorophenyl) -3-hydroxypropyl]-1- (4-hydroxyphenyl) -4- (4-methoxyphenyl) azetidin-2-one (11) was dissolved in 4ml absolute dimethylformamide. 210mg of powdered potassium carbonate and 42mg of 1, 4-butane sultone were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under oil pump vacuum, dichloromethane was added and washed once with water. The aqueous phase was acidified with 2N hydrochloric acid and extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was at 10g SiO₂Chromatography on column (dichloromethane/methanol 5/1). The product was obtained as an oil (72 mg).

C₂₉H₃₂FNO₇S ESIMS m/z：557(M⁺)

Example VI

4- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxoazetidin-2-yl } -phenoxy) butane-1-sulfonic acid (3)

250mg of 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]-4- (4-hydroxy-phenyl) azetidin-2-one (7) was dissolved in 6ml absolute dimethylformamide. Adding337mg of powdered potassium carbonate and 69. mu.l of 1, 4-butane sultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was at 10g SiO₂Chromatography on column (dichloromethane/methanol-5/1) and crystallization from ether. The product was obtained as a solid (131 mg).

C₂₈H₂₉F₂NO₆S ESIMS m/z：546(M⁺)

Example VII

3- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxoazetidin-2-yl } -phenoxy) propane-1-sulfonic acid (14):

250mg of 1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]-4- (4-hydroxy-phenyl) azetidin-2-one (7) was dissolved in 6ml absolute dimethylformamide. 337mg of powdered potassium carbonate and 59. mu.l of 1, 3-propane sultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was at 10g SiO₂Chromatography on column (dichloromethane/methanol-5/1) and crystallization from ether. The product was obtained as a solid (250 mg).

C₂₇H₂₇F₂NO₆S ESIMS m/z：532(M⁺)

Example VIII

(4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxoazetidin-2-yl } benzylcarbamoyl) methanesulfonic acid (18):

a)4- [5- (4-fluorophenyl) -1- (4-fluorophenylamino) -5-hydroxy-2- (2-oxo-4-phenyloxazolidine-3-carbonyl) -pentyl ] -benzonitrile (15):

2.5g of 3- [5- (4-fluorophenyl) -5-hydroxypentanoyl]-4-phenyloxazolidin-2-one in 30ml dichloromethane and 3.9g 4- [ (4-fluorophenylimino) -methyl]-benzonitrile and cooling the mixture to-10 ℃. 6.4ml of diisopropylethylamine were added and 4.05ml of trimethylchlorosilane were added to the mixture over 30 minutes, so that the temperature did not exceed-5 ℃. The mixture was stirred at this temperature for 1 hour and then cooled to-25 ℃. After which 0.8ml of titanium tetrachloride was slowly added. The black mixture was stirred at-25 ℃ to-30 ℃ overnight and then decomposed with 35ml of 7% tartaric acid solution, followed by stirring at room temperature for 1 hour. 15ml of a 20% sodium bicarbonate solution are then added and the mixture is stirred for a further 1 hour. After phase separation, the organic phase is washed with 30ml of water, dried over magnesium sulfate and concentrated to about 10 ml. Then 2ml of bis (trimethylsilyl) acetamide were added and the mixture was heated at reflux for 30 minutes and then concentrated under reduced pressure. The residue was crystallized from ethyl acetate/heptane. The product was filtered off with suction and dried under reduced pressure. The product (C) having a molecular weight of 653.81 is obtained₃₇H₃₇F₂N₃O₄Si)；MS(ESI⁺)：654.3(M+H⁺)，582.2(M+H⁺-Si(CH₃)₃)。

b) {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] 4-oxoazetidin-2-yl } -benzonitrile (16):

2g of 4- [5- (4-fluorophenyl) -1- (4-fluorophenylamino) -5-hydroxy-2- (2-oxo-4-phenyl-oxazolidine-3-carbonyl) -pentyl]-benzonitrile (15) is dissolved in 20ml of methyl tert-butyl ether and heated with 100mg of tetrabutylammonium fluoride trihydrate and 1.3ml of bis (trimethylsilyl) acetamide at 40 ℃ for about 1 hour. The reaction was monitored by thin layer chromatography. After the reaction was completed, 0.2ml of glacial acetic acid was first added and the mixture was stirred for 30 minutes and then concentrated. To the residue was added 20ml of a mixture of isopropanol/2N sulfuric acid ═ 10:1 and the mixture was stirred for 1 hour. Adding solid sodium bicarbonate with a spatula tip, and addingThe mixture was concentrated under reduced pressure, ethyl acetate was added to the residue and the organic phase was washed with water and dried, after removal of the solvent, the residue was purified by column chromatography (SiO)₂，CH₂Cl₂Methanol 100: 1). The product thus obtained has a molecular weight of 418.45 (C)₂₅H₂₀F₂N₂O₂)；MS(DCI⁺)：419(M+H⁺)。

c)4- (4-aminomethylphenyl) -1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -azetidin-2-one (17):

200mg of {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl group]-4-Oxoazetidin-2-yl } -benzonitrile (16) is dissolved in 20ml of ethanol and hydrogenated with 0.5ml of concentrated aqueous ammonia with Raney nickel under a hydrogen pressure of 75 bar and at 25 ℃ for 30 hours. The catalyst is removed by suction filtration, the mixture is concentrated under reduced pressure and the residue is purified by column chromatography (SiO)₂，CH₂Cl₂Methanol/concentrated NH₃100:10: 1). This product was obtained with a molecular weight of 422.5 (C)₂₅H₂₂F₂N₂O₂)；MS(DCI⁺)：423(M+H⁺)，405(M+H⁺-H₂O)。

d) (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] 4-oxoazetidin-2-yl } -benzylcarbamoyl) methanesulfonic acid (18):

120mg of 4- (4-aminomethylphenyl) -1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]-azetidin-2-one (17), 48. mu.l of diisopropylethylamine in 1ml of dimethylformamide was added to a solution of 40mg of sulfoacetic acid, 110. mu.l of diisopropylcarbodiimide, 76mg of hydroxybenzotriazole in 2ml of dimethylformamide, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) ═ 80/20 → 10/90). The product is obtained with a molecular weight of 544.58 (C)₂₇H₂₆F₂N₂O₆S₁)；MS(ESI)：527(M+H⁺-H₂O)。

Example IX

{4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) -4-oxoazetidin-1-yl ] -benzylcarbamoyl } methanesulfonic acid (19):

60mg of 1- (4-aminomethylphenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]A solution of-4- (4-methoxyphenyl) azetidin-2-one (5) in 1ml dimethylformamide is added to a solution of 20mg of sulfoacetic acid, 55. mu.l of diisopropylcarbodiimide, 38mg of hydroxybenzotriazole in 1ml dimethylformamide and the mixture is stirred at room temperature for 12 hours. The reaction mixture was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) ═ 80/20 → 10/90). The product is obtained with a molecular weight of 556.61 (C)₂₈H₂₉F₁N₂O₇S₁)；MS(ESI)：539.05(M+H⁺-H₂O)。

Example X

N- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -4-oxoazetidin-1-yl } -benzyl) succinamic acid (20):

100mg of 4- (4-aminomethylphenyl) -1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]A solution of azetidin-2-one (17), 33. mu.l triethylamine in 2ml dimethylformamide was added to a solution of 279mg succinic acid, 92. mu.l diisopropylcarbodiimide, 80mg hydroxybenzotriazole in 2ml dimethylformamide and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and separated by HPLC (Knauer Eu)rospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) ═ 80/20 → 10/90. The product is obtained with a molecular weight of 522.55 (C)₂₇H₂₆F₂N₂O₆S₁)；MS(ESI)：545.19(M+Na⁺)。

Example XI

{2- [2- ({4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) -4-oxoazetidin-1-yl ] benzylcarbamoyl } methoxy) ethoxy ] ethoxy } acetic acid (21):

64mg of 1- (4-aminomethylphenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]A solution of 4- (4-methoxyphenyl) azetidin-2-one (5), 21. mu.l triethylamine in 1ml dimethylformamide was added to a solution of 327mg 3, 6, 9 trioxaundecanedioic acid, 57. mu.l diisopropylcarbodiimide, 50mg hydroxybenzotriazole in 2ml dimethylformamide and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and separated by HPLC (knauer eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) ═ 80/20 → 10/90). The product is obtained with a molecular weight of 638.70 (C)₃₄H₃₉F₁N₂O₉)；MS(ESI)：639.27(M+H⁺)。

Example XII

4- ((3-carboxypropionyl) - {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxy-phenyl) -4-oxoazetidin-1-yl ] benzyl } amino) -4-oxobutanoic acid (22):

70mg of 1- (4-aminomethylphenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]4- (4-methoxybenzene)Yl) azetidin-2-one (5), 23. mu.l triethylamine in 1ml dimethylformamide were added to a solution of 190mg succinic acid, 63. mu.l diisopropylcarbodiimide, 55mg hydroxybenzotriazole in 2ml dimethylformamide and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) ═ 80/20 → 10/90). The product is obtained with a molecular weight of 634.4 (C)₃₄H₃₅F₁N₂O₉)；MS(ESI-neg.)：633.22(M-H⁺)。

Example XIII

11- {4- [3- [3- (4-fluorophenyl) -3-hydroxypropyl ] -2- (4-methoxyphenyl) -4-oxoazetidin-1-yl ] benzylcarbamoyl } undecanoic acid (23):

70mg of 1- (4-aminomethylphenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]A solution of 4- (4-methoxyphenyl) azetidin-2-one (5), 23. mu.l triethylamine in 1ml dimethylformamide was added to a solution of 371mg dodecanedioic acid, 63. mu.l diisopropylcarbodiimide, 55mg hydroxybenzotriazole in 2ml dimethylformamide and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) ═ 80/20 → 10/90). The product is obtained with a molecular weight of 646.81 (C)₃₈H₄₇F₁N₂O₆)；MS(ESI)：647.35(M+H⁺)。

Table 1: a compound of formula I

The activity of the compounds of formula I of the invention is determined using the following method:

determination of cholesterol absorption + using feces from mouse, rat or hamster ³ Effect of H-taurocholic acid excretion

NMRI mice, Wistar rats or Golden Syrian hamsters (divided into groups of n-4-6) were housed in metabolic cages where they were fed standard feed (Altromin, lage (lippe)). Administration of a radiotracer(s) (ii)¹⁴C-cholesterol), the feed was withdrawn and the animals were acclimatized to the grill.

In addition, test foods were orally administered (¹⁴C-cholesterol in20, Pharmacia-Upjohn) was used 24 hours before³H-TCA (taurocholic acid) (e.g., 1. mu. Ci/mouse to 5. mu. Ci/rat) subcutaneously labeled animals.

Cholesterol absorption test: 0.25 ml/mouse was orally administered through a mouth feeding tube20(Pharmacia-Upjohn) (0.25. mu. Ci in 0.1mg of cholesterol¹⁴C-cholesterol).

Test substances were prepared in 0.5% methylcellulose (Sigma)/5% Solutol (BASF, Ludwigshafen) or in a suitable vehicle. The test substance was administered in a volume of 0.5 ml/mouse. The test substance is administered to the test food immediately before¹⁴C-cholesterol labeled Intralipid) was administered prior (cholesterol absorption assay).

CollectingFeces over 24 hours: after 24 hours of measurement¹⁴C-cholesterol and³fecal exclusion of H-taurocholic acid (TCA).

The liver was removed and homogenized and an aliquot was incinerated in Oximate (model 307, Packard) to determine that it had been ingested/absorbed¹⁴The amount of C-cholesterol.

Evaluation:

stool sample:

the total weight was determined, samples were made to the indicated volume with water and then homogenized, aliquots were evaporated to dryness and incinerated in Oximate (model 307, Packard, for incineration of radiolabeled samples): will be radioactive³H-H₂O and¹⁴C-CO₂respectively extrapolated to excretion³H-taurocholic acid and¹⁴amount of C-cholesterol (dual isotope technique). ED as a dose from dose-response curves₂₀₀Values were interpolated as doses to double either TCA or cholesterol excretion based on a concurrently treated control group.

Liver samples:

liver uptake¹⁴The amount of C-cholesterol is based on the dose administered. Interpolation of ED from dose-response curves₅₀Value as liver uptake¹⁴Dosage at which C-cholesterol was halved (50%) based on control.

The following ED₅₀The values confirm the activity of the compounds of formula I according to the invention.

EXAMPLE No. ED₅₀(liver) [ mg/mouse]

I 1.0

II >0.1

IV 0.3

VIII 0.3

IX <1.0

X <1.0

XIII <0.1

XVIII 0.005

XXI 0.1

XXII 0.1

XXV 0.3

XXVIII 0.3

As shown in the table above, the compounds of formula I have very good cholesterol lowering effect.

Biological absorption:

bioabsorption of compounds of formula I was determined using the Caco cell model (a.r. hilgers et al, Caco-2 cell monolayer as a model of drug transport across the intestinal mucosa, pharm. res.1990, 7, 902).

From the data determined, it can be seen that the bioabsorption of the compounds of formula I according to the invention is significantly lower than that of the compounds described in the prior art (reference structure):

reference structure:

Ezetimibe

Claims (8)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein

R2, R4, R5, R6 are each independently of the others H, F, Cl, Br, I, (C)₁-C₆) Alkyl, O- (C)₁-C₆) -an alkyl group;

r1, R3 are independently of each other- (CH)₂)_0-1-Y-W-(C₀-C₂₅) -alkylene-Y '-W' - (LAG), and wherein one or more individual carbon atoms of the alkylene group are optionally replaced by-O-;

H、F、Cl、Br、I、(C₁-C₆) Alkyl, O- (C)₁-C₆) -an alkyl group;

y, W, Y ', W' are independently of each other NH, NCH₃O, O, one bond or S (O)_nWherein n is 0-2;

or Y-W or Y '-W' taken together are a bond,

(LAG) is- (CH)₂)_1-10-SO₃H、-(CH₂)_0-10-P(O)(OH)₂、(CH₂)_0-10-O-P(O)(OH)₂、-(CH₂)_0-10-COOH；

Wherein at least one of the radicals R1 or R3 must have- (CH) in each case₂)_0-1-Y-W-(C₀-C₂₅) -alkylene-Y '-W' - (LAG) meaning; wherein one or more individual carbon atoms of the alkylene group are optionally replaced by-O-;

but excluding the compound 2- { [4- (4- {1- (4-fluorophenyl) -3- [3- (4-fluorophenyl) -3-hydroxypropyl]-4-oxoazetidin-2-yl } phenoxy) butyl]Methylamino } ethanesulfonic acid and where the radicals R1-R6 have the meaning-O- (CH)₂)_1-10-COOH、(C₁-C₆) -alkylene-COOH or-COOH.

2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, wherein (LAG) is a carboxylic acid group or a sulfonic acid group.

3. A medicament containing one or more compounds as claimed in claim 1 or 2.

4. A process for the preparation of a medicament containing a compound as claimed in claim 1 or 2, which comprises mixing the active compound with a pharmaceutically acceptable carrier and bringing the mixture into a form suitable for administration.

5. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of hyperlipidemia.

6. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for lowering serum cholesterol concentration.

7. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of clinical manifestations of atherosclerosis.

8. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of insulin resistance.